The elderly population is the fastest growing element of our society, hence understanding the factors that contribute to cognitive decline is imperative, particularly as age is the major risk factor for several neurological disorders.  If nothing is done to alter the current course, the number of people suffering from age-dependent neurological disorders will increase substantially, which will exacerbate the already high socio-economical impact these diseases exert on our society.

Overall, we use broad genetic approaches to modify the genome of animals with the goal of understanding the role of specific neuronal populations and for elucidating the molecular mechanisms underlying age-dependent neurodegenerative disorders, such as Alzheimer’s disease and Frontotemporal dementia.  These genetic approaches include direct manipulation of the mouse genome through the development of inducible transgenic mice and viral transduction mechanisms.  Both of these approaches offer precise temporal control and regional specificity and can be superimposed with varying developmental stages of the CNS.  The outcome of these studies will reveal critical molecular determinants underlying motor and cognitive dysfunction in the mammalian CNS.

Particularly, we focus on two main areas of research:

Understanding the molecular mechanisms underlying the early cognitive deficit in Alzheimer’s disease.  Alzheimer’s disease (AD) is the most common neurodegenerative disorder.  The two hallmark lesions of AD are amyloid plaques, formed of a small peptide called Aβ, and neurofibrillary tangles, mainly composed of the hyperphosphorylated protein tau.  Compelling evidence indicates that Aβ plays a pivotal role in the cognitive decline in AD.  However, the molecular mechanisms underlying such phenomenon are largely unknown.  Using genetically modified mice and applying different molecular, genetic and pharmacological approaches, we aim at unveiling the early molecular changes occurring during the course of the disease.  Specifically, we focus on elucidating the role of selective signaling pathways (e.g., mTOR signaling) on the onset and progression of AD.

Understanding the molecular pathways underlying frontotemporal lobar degeneration.  Frontotemporal lobar degeneration (FTLD) is the second most common form of dementia in people under the age of 65.  Clinically, FTLD manifests with progressive behavioral and personality dysfunction that eventually culminates into a status of general cognitive impairment and dementia.  On a neuropathological examination the FTLD brains are characterized by a marked atrophy of the frontal and temporal lobe, neuronal loss and gliosis and the accumulation of abnormal proteinaceous inclusions.  Based on the biochemical composition of the cellular inclusions FTLD can be divided in two major groups: those cases characterized by the accumulation of hyperphosphorylated tau protein (tauopathies) and those cases characterized by the accumulation of the TAR DNA binding protein-43 (TDP-43), which are referred to as FTLD-TDP.

Different species of TDP-43 have been indentified and it has been suggested that pathologic TDP-43 is hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments that are only found in affected brain regions.  However, the data linking such fragments to the clinical phenotype are scarce and correlative rather than causative.  Indeed, it remains to be established if TDP-43 accumulation is the cause of the disease or if it is just a secondary event in the disease pathogenesis.  Understanding this difference has a profound clinical implication as it will guide the design of potential therapeutic targets.  Our goal is to understand the molecular pathways leading to the cognitive phenotype in FTLD and to identify the similarities and differences that lead to FTDP-tau versus FTD-TDP.  Toward this goal, two complementary approaches will be used: generation of new genetically-modified animal models and brain-somatic manipulation of tau, TDP-43 and progranulin expression.